Protein kinases are the enzymes which transfer a phosphate group from a nucleoside triphosphate to certain serine, threonine or tyrosine residues. Protein phosphorylation causes the activation of signal transduction pathways, which play crucial roles in various biological processes, including cell growth, metabolism, differentiation and death. It is known that abnormal signals caused by abnormal or improper activities of protein kinases are related to a number of diseases, including cancer, inflammation, autoimmune disease, metabolic disease, infection, central nervous system disease, cardiovascular disease and so on. Thus, protein kinases are attractive targets for drug development (Cohen, Nat. Rev. Drug Discovery 2002, 1, 309).
The abl gene and the bcr gene are normal genes located on chromosome 9 and 22, respectively. Two fusion genes are created by the reciprocal translocation between these two genes: the bcr-abl gene located on chromosome 22q- and the abl-bcr gene located on chromosome 9q+. The protein of 210 kD (p210Bcr-Abl) is encoded by the bcr-abl gene on the Philadelphia chromosome. The Abl part of the Bcr-Abl protein comprising the Abl tyrosine kinase is strictly regulated in the prototype c-Abl but continuously activated in the Bcr-Abl fusion protein, which results in cell growth disorder. The Bcr-Abl protein can be found in 95% of the patients with Chronic Myelogenous Leukemia (CML) and in 10-25% of the patients with Acute Lymphoblastic Leukemia (ALL). Imatinib, brand-named as Gleevec, is a Bcr-Abl tyrosine kinase inhibitor and has been clinically proven to be an effective formulation for the treatment of CML. (Druker et al. N. Engl. J. Med. 2006, 355, 2408). However, despite continuous treatment using Imatinib, some patients with CMLs are recurrent at the terminal phase or the blast crisis phase due to drug resistance. The molecular basis of drug resistance is that imatinib-resistant mutants arise in the kinase domain of the Bcr-Abl protein. To date, more than 22 mutants have been reported and the most common ones are M244V, G250E, Q252H, Y253H, E255K, E255V, F311L, T351I, F317L, F359V, V379I, L387M, H396P, H396R and etc. (Nardi, et al. Curr. Opin. Hematol. 2004, 11, 35).
c-Kit (CD117, stem cell factor receptor), encoded by the c-kit proto-oncogene, is a kind of growth factor receptor with tyrosine kinase activity. It can be activated upon binding to stem cell factor (SCF). Mutations in c-kit result in continuous activation of the function of c-Kit tyrosine kinase, which further causes the activity of tyrosine kinase independent on ligands, the autophosphorylation of c-Kit, and the deregulation of cell proliferation. Overexpression and mutations of c-Kit are found in most gastrointestinal stromal tumors (GIST). Gastrointestinal stromal tumors are a series of mesenchymal tumors which arise from the precursors of gastrointestinal tract tissue cells. They mainly occur in the middle-aged and the old population. About 70% of the tumors occur in the stomach, 20-30% of the tumors occur in the small intestine and less than 10% of the tumors occur in the esophagus, colon and rectum. As known to all, gastrointestinal stromal tumors are resistant to classical chemotherapy but can be treated effectively by inhibiting c-Kit using Imatinib, which suggests that c-Kit plays a vital role in the pathogenesis of these diseases (Joensuu et al. N. Engl. J. Med. 2001, 344, 1052). c-Kit is overexpressed and mutates in other various human cancers as well, including mast cell tumor, neuroblastoma, germ cell tumor, melanoma, small cell lung cancer, breast cancer, oophoroma and acute myeloid leukaemia (see Edling et al. Int. J. Biochem. Cell Biol. 2007, 39, 1995; Lennartsson et al. Curr. Cancer Drug Targets, 2006, 6, 65).
In addition to the role in cancers, SCF/c-Kit also related to autoimmune or inflammatory diseases. SCF is expressed by various structural and inflammatory cells in the breathing passage. A number of pathways are activated by the combination of SCF and c-Kit, including the pathways involving Phosphoinositide-3 (PI3) kinase, phospholipase C (PLC)-gamma, Src protein kinase, Janus kinase (JAK)/signal transducers and activators of transcription (STAT) and mitogen-activated protein (MAP) kinase. Suppression of the SCF/c-Kit pathway can dramatically lower the level of histamine, reduce the penetration of mast cells and eosinophilic granulocytes, and decrease the release of interleukin (IL)-4 and the over-reactivity of the breathing passages. SCF/c-Kit is therefore a potential treatment target, which can control the number of mast cells and eosinophilic granulocytes, and can control the activation of autoimmune or inflammatory diseases, including scytitis, rheumatoid arthritis, allergic rhinitis, asthma, ankylosing spondylitis, psoriasis and Crohn disease (see Reber et al. Eur. J. Pharmacol. 2006, 533, 327; Paniagua et al. Nat. Clin. Prac. Rheum. 2007, 3, 190).
Platelet-derived growth factor receptors (PDGFR), such as PDGFR-α and PDGFR-β, are transmembrane tyrosine kinase receptors, whose ligands are formed by two A chains (PDGF-A), or two B chains (PDGF-B), or a heterodimer of one A chain and one B chain (PDGF-AB). Platelet-derived growth factor receptors are dimerized upon ligands binding, followed by activation of its tyrosine kinase and signaling to downstream. In vivo animal studies on PDGFs and PDGFRs reveal that PDGFR-α signaling plays a role in the development of gastrulation, cranial and cardiac neural crest, gonad, lung, intestine, skin, central nervous system and bone. Similarly, the role of PDGFR-β signaling in angiogenesis and early hematopoiesis has been revealed as well. Platelet-derived growth factor signaling is associated with a number of diseases. Autocrine activation of growth factor signaling pathway relates to some gliomatosis cerebri, myeloproliferative disease, tumor, multiple myeloma, and sarcoma including dermatofibrosarcoma protuberans. Paracrine growth factor signaling is usually found in epithelial cancer. It initiates the inhalation of matrix therein, and may participate in the epithelial-mesenchymal transition and thus affect tumor's development, angiogenesis, invasion and metastasis. Platelet-derived growth factors drive organic pathological changes of vascular disease, such as atheromatosis, arteriostenosis, pulmonary hypertension, retinal disease, and hepatofibrosis including pulmonary interstitial fibrosis, hepatocirrhosis, scleriasis, glomerulosclerosis and myocardial fibrosis (see Andrae et al. Gene Dev. 2008, 22, 1276). Therefore, the suppression of PDGFR can prevent and treat the above-mentioned diseases. Additionally, the suppression of PDGFR can also treat a variety of autoimmune or inflammatory diseases including diabetes, particularly Type-I diabetes, rheumatoid arthritis, psoriasis, Crohn disease and etc (Paniagua et al. Nat. Clin. Prac. Rheum. 2007, 3, 190; Louvet et al. Proc. Natl. Acad. Sci. USA, 2008, 105, 18895).
The invention provides a novel kind of dihydroindene amide derivatives, which can inhibit the activity of protein kinases, especially one or more protein kinases described above. These compounds will therefore be useful to prevent or treat the diseases associated with the abnormality or disorder in the activity of protein kinases, especially the diseases associated with abnormality in the activity of Abl, Bcr-Abl, c-Kit and PDGFR protein kinases.